TY - JOUR
T1 - UV-light-induced conversion and aggregation of prion proteins
AU - Redecke, Lars
AU - Binder, Stephan
AU - Elmallah, Mohammed I.Y.
AU - Broadbent, Rebecca
AU - Tilkorn, Claudia
AU - Schulz, Benjamin
AU - May, Patrick
AU - Goos, Arne
AU - Eich, Andreas
AU - Rübhausen, Michael
AU - Betzel, Christian
N1 - Funding Information:
The authors thank Ilka Mahns, Inke Magens, Phillip Opelka, and Lisa Krell for excellent technical assistance during the UV-irradiation experiments. S.B. thanks the University of Hamburg for financial support. Funding was provided by NATO via Grant CGP.EAP.CLG.982543 (to C.B.).
Copyright:
Copyright 2009 Elsevier B.V., All rights reserved.
PY - 2009/5/15
Y1 - 2009/5/15
N2 - Increasing evidence suggests a central role for oxidative stress in the pathology of prion diseases, a group of fatal neurodegenerative disorders associated with structural conversion of the prion protein (PrP). Because UV-light-induced protein damage is mediated by direct photo-oxidation and radical reactions, we investigated the structural consequences of UVB radiation on recombinant murine and human prion proteins at pH 7.4 and pH 5.0. As revealed by circular dichroism and dynamic light scattering measurements, the observed PrP aggregation follows two independent pathways: (i) complete unfolding of the protein structure associated with rapid precipitation or (ii) specific structural conversion into distinct soluble β-oligomers. The choice of pathway was directly attributed to the chromophoric properties of the PrP species and the susceptibility to oxidation. Regarding size, the oligomers characterized in this study share a high degree of identity with oligomeric species formed after structural destabilization induced by other triggers, which significantly strengthens the theory that partly unfolded intermediates represent initial precursor molecules directing the pathway of PrP aggregation. Moreover, we identified the first suitable photo-trigger capable of inducing refolding of PrP, which has an important biotechnological impact in terms of analyzing the conversion process on small time scales.
AB - Increasing evidence suggests a central role for oxidative stress in the pathology of prion diseases, a group of fatal neurodegenerative disorders associated with structural conversion of the prion protein (PrP). Because UV-light-induced protein damage is mediated by direct photo-oxidation and radical reactions, we investigated the structural consequences of UVB radiation on recombinant murine and human prion proteins at pH 7.4 and pH 5.0. As revealed by circular dichroism and dynamic light scattering measurements, the observed PrP aggregation follows two independent pathways: (i) complete unfolding of the protein structure associated with rapid precipitation or (ii) specific structural conversion into distinct soluble β-oligomers. The choice of pathway was directly attributed to the chromophoric properties of the PrP species and the susceptibility to oxidation. Regarding size, the oligomers characterized in this study share a high degree of identity with oligomeric species formed after structural destabilization induced by other triggers, which significantly strengthens the theory that partly unfolded intermediates represent initial precursor molecules directing the pathway of PrP aggregation. Moreover, we identified the first suitable photo-trigger capable of inducing refolding of PrP, which has an important biotechnological impact in terms of analyzing the conversion process on small time scales.
UR - http://www.scopus.com/inward/record.url?scp=64649088618&partnerID=8YFLogxK
U2 - 10.1016/j.freeradbiomed.2009.02.013
DO - 10.1016/j.freeradbiomed.2009.02.013
M3 - Journal articles
C2 - 19249347
AN - SCOPUS:64649088618
SN - 0891-5849
VL - 46
SP - 1353
EP - 1361
JO - Free Radical Biology and Medicine
JF - Free Radical Biology and Medicine
IS - 10
ER -
